Use of tetrandrine to differentiate between mechanisms involved in silica-versus bleomycin-induced fibrosis

Citation
Jyc. Ma et al., Use of tetrandrine to differentiate between mechanisms involved in silica-versus bleomycin-induced fibrosis, J TOX E H A, 57(4), 1999, pp. 247-266
Citations number
46
Categorie Soggetti
Environment/Ecology,"Pharmacology & Toxicology
Journal title
JOURNAL OF TOXICOLOGY AND ENVIRONMENTAL HEALTH-PART A
ISSN journal
15287394 → ACNP
Volume
57
Issue
4
Year of publication
1999
Pages
247 - 266
Database
ISI
SICI code
1528-7394(19990625)57:4<247:UOTTDB>2.0.ZU;2-8
Abstract
Animals exposed to silica or bleomycin (BLM) develop pulmonary fibrosis. Te trandrine (TT) has been shown to inhibit stimulant-induced macrophage respi ratory burst and effectively reduce silica-induced lung injury. The present study employed TT as a probe to assess the differences in mechanisms invol ved in silica- and BLM-induced pulmonary responses. Rats received a single intratracheal instillation of silica 140 mg/rat, sacrificed 4 wk postexposu re or BLM ii mg/kg or similar to 0.25 mg/rat, sacrificed up to 2 wk postexp osure. TT was administered orally at 18 mg/kg, 3 times/wk for desired time periods beginning 5 d before silica or BLM exposure. Both the silica and BL M exposures resulted in a significant increase in lung weight, total protei n, lactate dehydrogenase (LDH), and phospholipids (PL) content in the acell ular fluid from the first lavage, and hydroxyproline content in the lung ti ssue. Alveolar macrophages (AM) isolated from rats exposed to silica or BLM exhibited significant increases in secretion of interieukin-1 (IL-1), tumo r necrosis factor a TNF-alpha, and transforming growth factor beta TGF-beta . TT treatment significantly lowered the silica- or BLM-induced increase in lung weight, while marginally reducing the release of IL-1 and TNF-alpha b y AM. TT, however, markedly inhibited the silica-induced increase in the ac ellular protein, LDH and PI, hydroxyproline content, and the production of TGF-beta by AM but had no marked effect on these same parameters in SIM-exp osed rats. Histological examination of rats exposed to BLM for 14 d showed pulmonary inflammation and fibrosis. TT treatment had only a small effect o n limiting the extent of these lesions and did not significantly affect the ir severity. In summary, data indicate that many inflammatory and fibrotic effects of in vivo silica exposure are substantially attenuated by TT, wher eas the stimulation by BLM is only marginally affected by this drug. Since TT acts to attenuate AM-mediated reactions, these results suggest that AM m ay play a pivotal role in silica-induced fibrotic development and may be le ss involved in the pathogenesis of BLM-induced fibrosis.